The goal of cancer treatment is cure without morbidity. Radiation can be an effective locoregional cancer treatment. The challenge is to deliver the appropriate dose to only the tumor without exposing normal tissues to excessive dose. Protons, with no exit dose beyond the target, irradiate less normal tissue than comparable photon fields. This can improve the therapeutic ratio of cure vs. complication. While many patients have been treated with protons with impressive clinical results in a number of disease sites, and while protons have in fact become widely accepted in some clinical scenarios, further research can greatly enhance the clinical effectiveness and applicability of protons, particularly through intensity-modulated proton therapy (IMPT). IMPT is a powerful tool with unique opportunities to improve both outcomes the understanding of physical and biophysical aspect of protons through its markedly different dose patterns. The primary objective of this multi-institutional program project is to study and refine IMPT to improve outcome in randomized phase II trials for cancers of the lung, liver, oropharynx, nasopharynx and brain; and in non-randomized phase l/ll trials for pediatric CNS tumors needing craniospinal irradiation, retroperitoneal sarcoma, breast, atypical and malignant meningioma, and glioblastoma. This project supports the mission of the NCI to improve the treatment and continuing care of cancer patients. The hypothesis is that through better understanding of the proton interactions with tissues, and study and management of motion and anatomic changes, higher accuracy in proton therapy (PT) can be achieved to further improve target coverage, reduce the dose bath and elaborate and manage biophysical determinants of treatment response. Four integrated projects are proposed: (1) Assessment of the Effectiveness of IMPT vs. IMRT through Randomized Clinical Trials; (2) Exploratory Phase l/ll Clinical Studies to Improve the Therapeutic Ratio of PT; (3) Assessing and Understanding the Impact of Physical and Biological Factors on Outcomes of PT; and (4) Improving Outcomes by Optimally Exploiting Physical and Biological Characteristics of Protons.